This invention is directed to treating a patient with asthma to ameliorate the symptoms thereof, to treating patients with mild or moderate asthma to inhibit progression to more severe asthma, and to reducing corticosteroid requirements in patients with severe asthma.
About 10 million asthmatics live in the USA. Asthma sufferers are subject to acute attacks characterized by increased responsiveness of the tracheobronchial tree to various stimuli, which leads to generalized airway constriction manifested by dyspnea, cough and wheezing. Asthma sufferers often experience acute exacerbations of bronchoconstriction, which may be life-threatening. The degrees of severity of an acute asthma attack have been classified as mild, moderate and severe in NIH Publication No. 97-4051 (April 1997) of the National Heart, Lung and Blood Institute of the National Institutes of Health and these classifications are used herein and NIH Publication No. 97-4051 is incorporated herein by reference.
A patient presenting with severe asthma is treated with a series of drugs including inhaled beta2-agonist and anticholinergic and systemic corticosteroid medications, and is given oxygen to achieve O2 saturation xe2x89xa790%. Any patient with impending or actual respiratory failure is treated with parenteral beta2-agonist, inhaled anticholinergic and parenteral corticosteroid medications, and if no favorable response is shown, by endotracheal intubation and mechanical ventilation and treatment in an intensive care unit. Annually several thousand patients with severe asthma die.
Elder et al. U.S. Pat. No. 5,603,963 states xe2x80x9cRecently, gold-based drugs, particularly Auranofin, have also been used to treat asthma . . . .xe2x80x9d Auranofin is (1-thio-beta-D-glucopyranose-2,3,4,6-tetraacetato-S) (triethylphosphine)gold. No therapeutic mechanism for this drug is said to have been clearly established.
It is an object herein to provide novel methods for treating a patient with asthma to ameliorate the symptoms thereof and to treat patients with mild or moderate asthma to inhibit progression to more severe asthma.
It is an object of one embodiment herein to provide a method for treating severe asthma which reduces corticosteroid requirements.
The invention herein is based on the discoveries that severe asthma is associated with a deficiency of endogenous S-nitrosothiols (whereas NO levels are known to be high), that airway tissue contains activities, including enzymatic activities, which break down S-nitrosothiols to NO suggesting that such activities may be elevated in the case of asthma, that activities that break down S-nitrosothiols to NO and other low mass nitrogen oxides attenuate their bronchodilator activity, and that agents which inhibit catalyst for S-nitrosothiol breakdown restore the bronchodilator activity.
In one embodiment, the invention herein is directed to a method for treating a patient with asthma to ameliorate symptoms thereof comprising administering to said patient (a) a therapeutically effective amount of an inhibitor of S-nitrosothiol breakdown except for the gold-containing compounds heretofore used to treat asthma including aurothioglucose, gold sodium thiomalate, and (1-thio-beta-D-glucopyranose-2,3,4,6-tetraacetato-S)(triethylphosphine)gold (Auranofin) or (b) therapeutically effective amounts of an NO donor and of an inhibitor of S-nitrosothiol breakdown, or (c) a therapeutically effective amount of an NO donor which is itself an S-nitrosothiol or which generates on S-nitrosothiol in vivo which is resistant to breakdown by catalysts which cause S-nitrosothiol breakdown.
In another embodiment herein the administrations of (a), (b) or (c) are carried out for the treatment of severe asthma in combination with systemic administration of a therapeutically effective amount of corticosteroid which is 10-80% of the dose of systemic corticosteroid utilized for the treatment of severe asthma if administrations of (a) or (b) or (c) are not utilized.
In still another embodiment, the invention herein is directed to a method for treating patients with mild or moderate asthma to inhibit progression to more severe asthma comprising administering to said patient (a) a therapeutically effective amount of an inhibitor of S-nitrosothiol breakdown except for gold containing compounds heretofore used to treat asthma including aurothioglucose, gold sodium thiomalate and (1-thio-beta-D-glucopyranose-2,3,4,5-tetraacetato-S)(triethylphosphine)gold (Auranofin) or (b) therapeutically effective amounts of an NO donor and of an inhibitor of S-nitrosothiol breakdown or (c) a therapeutically effective amount of an No donor which is itself an S-nitrosothiol or which generates an S-nitrosothiol in vivo which is resistant to breakdown by catalysts which cause S-nitrosothiol breakdown.
Gold-containing compounds which have heretofore been used to treat asthma are excluded in (a), above, to provide novelty. Administration of inhibitors of S-nitrosothiol breakdown different from these gold-containing compounds is not obvious from prior art administration of gold-containing compounds to treat asthma because the therapeutic mechanism of action of said gold-containing compounds in treating asthma has not heretofore been known. Gold-containing compounds are not excluded from inhibitors of nitrosothiol breakdown in (b), above, for the broad invention because gold-containing compounds have not heretofore been administered in combination with NO donors to treat asthma. While S-nitrosothiols have been administered previously to those with asthma to relax non-vascular smooth muscle including airway smooth muscle (see Stamler et al. U.S. Pat. Nos. 5,380,758; 5,574,068; 5,593,876 and 5,612,314), they have not been administered in combination with agents that prevent S-nitrosothiol breakdown to replace or add to the function of endogenous S-nitrosothiols. The combination is not obvious because it was not heretofore appreciated that S-nitrosothiols are subject to accelerated breakdown in asthma and that the combining of S-nitrosothiols with breakdown inhibitors makes more S-nitrosothiol available and provides synergistic result.
The term xe2x80x9cS-nitrosothiolxe2x80x9d is used herein to mean organic compound with NO group bonded to S.
The term xe2x80x9cS-nitrosothiol breakdownxe2x80x9d is used herein to mean a biologic process that causes decomposition of S-nitrosothiols such that they have less or no non-vascular smooth muscle relaxing effect. Both enzymatic and non-enzymatic processes are embraced. In one embodiment herein, non-enzymatic breakdown by superoxide is excluded.
The term xe2x80x9cinhibitor of S-nitrosothiol breakdownxe2x80x9d is used herein to mean a treating agent which inhibits decomposition of S-nitrosothiol breakdown so that the smooth muscle relaxing effect of the S-nitrosothiol persists longer.
The term xe2x80x9ctherapeutically effective amountxe2x80x9d is used herein to mean an asthma symptom ameliorating effective amount and, in-the case of patients with mild or moderate asthma, an amount effective to inhibit progression to more severe asthma. In all cases, a therapeutically effective amount is also an amount that effects an increase in S-nitrosothiol concentration or efficacy in airway tissue.